Process for preparing arylaminopropanols

ABSTRACT

The invention relates to a process for preparing enantiomerically enriched arylaminopropanols and to their use and also to intermediates.

This application is a division of U.S. Ser. No. 10/391,348, filed Mar.18, 2003, now pending; which claims foreign priority of German PatentApplication 102 12 301.2, filed Mar. 20, 2002.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a process for preparing enantiomericallyenriched aryl-aminopropanols and to their use and also to intermediates.

2. Description of Related Art

1-Aryl-3-aminopropan-1-ols have gained industrial significance inparticular as intermediates for the preparation of pharmaceuticals. Forexample, some 1-aryl-3-aminopropan-1-ols serve as precursor substancesfor the preparation of serotonin or noradrenaline takeup inhibitors. Inthe case of some of these inhibitors, it could be proven that certainenantiomers are not only inactive or less active, but may also evenexhibit undesired side effects (U.S. Pat. No. 5,104,899).

Corey and Reichard (Tetrahedron Letters, 39, 5207, 1989) describe aprocess for preparing S-fluoxetine in which, in an important step,3-chloropropiophenone is asymmetrically reduced using a chiral borane togive S-3-chloro-1-phenyl-1-propanol.

After reaction with sodium iodide and methylamine,(S)-3-(methylamino)-1-phenylpropan-1-ol is then obtained which may thenbe reacted further to the end product. Disadvantages of this process arethat expensive reagents have to be used, and that the overall yield isonly 77 to 82%.

A process for preparing enantiomerically enriched(1S)-3-(methylamino)-1-(2-thiophen-yl)-1-propanol starting from1-(2-thiophen-yl)-3-chloropropan-1-one is described in Chirality 2000,12, 26-29. After the reduction to racemic3-chloro-1-(2-thienyl)-1-propanol, the racemate is enzymaticallyseparated and the (S)-enantiomer is further reacted with NaI andmethylamine to give (S)-3-(methylamino)-1-(2-thiophen-yl)-propan-1-ol.This method has the disadvantage that enzymatic racemate separations canin principle only provide 50% of the desired enantiomer and the overallyield is therefore economically unacceptable.

A similar synthetic route is described in J. Lab. Comp. Radiopharm.1995, 36, 213-223, in which 1-(2-thiophen-yl)-3-chloropropan-1-one isasymmetrically reduced with borane and an oxazaborolidine. The yield inthis step is only 61%, which makes the overall process uneconomic.

There was therefore a need for an efficient and widely applicableprocess for preparing enantiomerically enriched arylaminopropanols whichstarts from reactants obtainable in a simple manner.

SUMMARY OF THE INVENTION

A process has now been found for preparing enantiomerically enrichedcompounds of the formula (I)

Ar—CH(OH)—CH₂—CH₂—NR¹R²  (I)

where

-   Ar is a substituted or unsubstituted aryl radical and-   R¹ and R² are each independently hydrogen, C₁-C₂₀-alkyl, C₄-C₁₄-aryl    or C₅-C₁₅-arylalkyl, or the two R¹ and R² radicals together are    C₃-C₁₂-alkylene,    characterized in that-   a) compounds of the formula (II) are converted to enantiomerically    enriched compounds of the formula (III) or compounds of the    formula (IV) are converted to enantiomerically enriched compounds of    the formula (V)

Ar—CO—CH₂—COOR³  (II)

Ar—CH(OH)—CH₂—COOR³  (III)

Ar—CO—CH₂—CONR¹R²  (IV)

Ar—CH(OH)—CH₂—CONR¹R²  (V)

-   -   where, in each case,    -   Ar is as defined under the formula (I) and    -   R¹ and R² are each as defined under the formula (I) and    -   R³ is hydrogen, C₁-C₂₀-alkyl, C₄-C₁₄-aryl or C₅-C₁₅-arylalkyl,        and where the reaction is effected        -   in the presence of a transition metal catalyst        -   with hydrogen or a hydrogen-transferring compound or a            mixture thereof and

-   b) in the case that compounds of the formula (II) have been used for    step a), the enantiomerically enriched compounds of the    formula (III) are reacted with amines of the formula (VI)

HNR¹R²  (VI)

-   -   where R¹ and R² are each as defined under the formula (I) to        give enantiomerically enriched compounds of the formula (V) as        defined above and

-   c) the enantiomerically enriched compounds of the formula (V) are    converted by reduction to enantiomerically enriched compounds of the    formula (I) as defined above.

It is pointed out that the scope of the invention also encompasses anydesired combinations of the ranges and areas of preference specified foreach feature.

For the purposes of the invention, enantiomerically enriched refers toenantiomerically pure compounds or mixtures of enantiomers of a compoundin which one enantiomer is present in an enantiomeric excess, alsoreferred to hereinbelow as ee (enantiomeric excess), in comparison tothe other enantiomer. This enantiomeric excess is preferably 10 to 100%ee, particularly preferably 60 to 100% ee and very particularlypreferably 85 to 100% ee.

For the purposes of the invention, enantiomerically enriched relates inparticular to the configuration of the carbon which is adjacent to theAr radical.

DETAILED DESCRIPTION OF THE INVENTION

In the formulae (I) to (V), Ar is preferably a carbocyclic aromaticradical having 6 to 24 framework carbon atoms or a heteroaromaticradical having 4 to 24 framework carbon atoms in which no, one, two orthree framework carbon atoms per cycle, but at least one frameworkcarbon atom in the entire heteroaromatic radical, may be substituted byheteroatoms selected from the group of nitrogen, sulphur or oxygen.

The carbocyclic aromatic radicals or heteroaromatic radicals may also besubstituted by up to five identical or different substituents per cycleselected from the group of hydroxyl, fluoro, nitro, cyano, free orprotected formyl, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl, C₅-C₁₄-aryl,C₆-C₁₅-arylalkyl, —PO—[(C₁-C₈)-alkyl]₂, —PO—[(C₅-C₁₄)-aryl]₂,—PO—[(C₁-C₈)-alkyl)(C₅-C₁₄)-aryl)], tri(C₁-C₈-alkyl)siloxyl or a radicalof the general formula (VII)

A-B-D-E  (VII)

where, each independently,A is missing or is a C₁-C₈-alkylene radical andB is missing or is oxygen, sulphur or NR⁴,

-   -   where R⁴ is hydrogen, C₁-C₈-alkyl, C₆-C₁₅-arylalkyl or        C₅-C₁₄-aryl and        D is a carbonyl group and

E is R⁵, OR⁵, NHR⁶ or N(R⁶)₂,

-   -   where R⁵ is C₁-C₈-alkyl, C₆-C₁₅-arylalkyl, C₁-C₈-haloalkyl or        C₅-C₁₄-aryl and    -   R⁶ is in each case independently C₁-C₈-alkyl, C₆-C₁₅-arylalkyl        or C₆-C₁₄-aryl, or N(R⁶)₂ together is a cyclic amino radical,        or a radical of the general formulae (VIIIa-e)

A-E  (VIIIa)

A-SO₂-E  (VIIIb)

A-B-SO₂R²  (VIIIc)

A-SO₃W  (VIIId)

A-COW  (VIIIe)

where A, B, E and R² are each as defined above and W is OH, NH₂ or OMwhere M is an alkali metal ion, half an equivalent of an alkaline earthmetal ion, an ammonium ion or an organic ammonium ion.

Particularly preferably, in the formulae (I) to (V) Ar is a monocyclicor bicyclic carbocyclic aromatic radical having a total of 6 to 14framework carbon atoms or a mono- or bicyclic heteroaromatic radicalhaving 4 to 12 framework carbon atoms in which no, one, two or threeframework carbon atoms per cycle, but at least one framework carbon atomin the entire heteroaromatic radical, may be substituted by heteroatomsselected from the group of nitrogen, sulphur or oxygen, and where themono- or bicyclic aromatic radical may be substituted by no, one, two orthree radicals per cycle, each of which is independently selected fromthe group of hydroxyl, C₁-C₁₂-alkyl, cyano, COOH, COOM,COO—(C₁-C₁₂-alkyl), COO—(C₄-C₁₀-aryl), CO—(C₁-C₁₂-alkyl),CO—(C₄-C₁₀-aryl), O—(C₁-C₁₂-alkyl), (C₁-C₁₂-alkyl)-O—(C₁-C₁₂-alkyl),(C₄-C₁₀-aryl)-O—(C₁-C₁₂-alkyl), O—(C₄-C₁₀-aryl), O—CO—(C₄-C₁₀-aryl),O—CO—(C₁-C₁₂-alkyl), OCOO—(C₁-C₁₂-alkyl), N—(C₁-C₁₂-alkyl)₂,NH—(C₁-C₁₂-alkyl), N(C₄-C₁₀-aryl)₂, NH—(C₄-C₁₀-aryl), fluorine,chlorine, bromine, NO₂, SO₃H, SO₃M, SO₂(C₁-C₁₂-alkyl), SO(C₁-C₁₂-alkyl),C₁-C₁₂-fluoroalkyl where fluoroalkyl is a singly, multiply or fullyfluorine-substituted alkyl radical as defined above,NHCO—(C₁-C₁₂-alkyl), CONH₂, CONH—(C₁-C₁₂-alkyl), NHCOO—(C₁-C₁₂-alkyl),PO(C₄-C₁₀-aryl)₂, PO(C₁-C₁₂-alkyl)₂, PO₃H₂, PO₃M₂, PO₃HM,PO(O(C₁-C₁₂-alkyl)₂ where M is in each case an alkali metal ion or halfan equivalent of an alkaline earth metal ion.

Very particularly preferably, aryl is phenyl, 2- or 3-thiophenyl, 2- or3-furanyl, 2- or 3-pyrrolyl, 3- or 4-pyrazolyl, 1-, 2-, or 4-thiazolyl,1-, 2-, or 4-oxazolyl, 2-, 4- or 5-imidazolyl, 2-, 3-, or 4-pyridyl, 2-or 3-pyrazinyl, 2-, 4-, or 5-pyrimidyl, 3-, 4-, 5- or 6-pyridazinyl, 2-or 3-indolyl, 3-indazolyl, indazolyl, 2- or 3-benzofuranyl, 2- or3-benzothiophen-yl, 2-, 3- or 4-quinolinyl, isoquinolinyl 2-, 4-, 6- or7-pteridinyl or 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrenyl whereeach of the radicals mentioned bears no, one or two radicals per cycle,each of which is independently selected from the group of C₁-C₄-alkyl,cyano, COO—(C₁-C₄-alkyl), O—(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂,NH—(C₁-C₄-alkyl), fluorine, chlorine, bromine or C₁-C₄-fluoroalkyl, forexample trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl.

Even greater preference is given to Ar being 2-thiophen-yl.

R¹ and R² in the formulae (I), (IV), (V) and (VI) are preferably eachindependently hydrogen, methyl, ethyl, isopropyl, phenyl or benzyl.

NR¹R² as a whole in the formulae (I), (IV) and (V) is particularlypreferably methylamino, ethylamino and isopropylamino, and, in formula(VI), HNR¹R² is methylamine, ethylamine and isopropylamine.

NR¹R² as whole in the formulae (I), (IV) and (V) is very particularlypreferably methylamino, and, in formula (VI), HNR¹R² is methylamine.

R³ in the formulae (II) and (III) is in each case preferably hydrogen,methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, isobutyl,phenyl or benzyl, although particular preference is given to methyl andethyl, and very particular preference to methyl.

Preferred compounds of the formula (II) for the process according to theinvention are:

methyl 3-oxo-3-(2-thienyl)propanoate, ethyl3-oxo-3-(2-thienyl)propanoate, isopropyl 3-oxo-3-(2-thienyl)propanoate,tert-butyl 3-oxo-3-(2-thienyl)propanoate, 2-ethylhexyl3-oxo-3-(2-thienyl)propanoate, methyl 3-oxo-3-(phenyl)propanoate, ethyl3-oxo-3-(phenyl)propanoate, isopropyl 3-oxo-3-(phenyl)propanoate,tert-butyl 3-oxo-3-(phenyl)propanoate, 2-ethylhexyl3-oxo-3-(phenyl)propanoate, methyl 3-oxo-3-(4-tolyl)propanoate, ethyl3-oxo-3-(4-tolyl)propanoate, isopropyl 3-oxo-3-(4-tolyl)propanoate,tert-butyl 3-oxo-3-(4-tolyl)propanoate and 2-ethylhexyl3-oxo-3-(4-tolyl)propanoate.

Preferred compounds of the formula (IV) for the process according to theinvention are:

3-oxo-3-(phenyl)propanamide, N-methyl-3-oxo-3-(phenyl)propanamide,N-benzyl-3-oxo-3-(phenyl)propanamide,N,N-dimethyl-3-oxo-3-(phenyl)propanamide, 3-oxo-3-(4-tolyl)propanamide,N-methyl-3-oxo-3-(4-tolyl)propanamide,N-benzyl-3-oxo-3-(4-tolyl)propanamide,N,N-dimethyl-3-oxo-3-(4-tolyl)propanamide,3-oxo-3-(2-thienyl)propanamide, N-methyl-3-oxo-3-(2-thienyl)propanamideand N-benzyl-3-oxo-3-(2-thienyl)propanamide.

For the process according to the invention, preference is given to usingcompounds of the formula (II) in step a) having the definitions andareas of preference specified above.

For the process according to the invention, particular preference isgiven to using compounds of the formula (II) in step a) having thedefinitions and areas of preference specified above for Ar and R¹ and,in step b), to reacting with methylamine.

The compounds of the formula (II) which can be used for the processaccording to the invention may be obtained, for example, by reactingcompounds of the formula (IX)

Ar—CO—CH₃  (IX)

where Ar has the same definition and areas of preference specified underthe formula (I)with compounds of the formula (X)

R³—O—CO—OR³  (X)

where the R³ radicals each independently have the same definition andareas of preference as stated under the formula (II).

An example is the reaction of 2-acetylthiophene with dimethyl carbonate,diethyl carbonate, diphenyl carbonate or dibenzyl carbonate.

The compounds of the formula (IV) which can be used for the processaccording to the invention may be obtained in a similar manner to thecompounds of the formula (II), for example, by base-catalysed reactionof compounds of the formula (IX) with compounds of the formula (XI)

R³—O—CO—NR¹R²  (XI)

where R¹, R² and R³ radicals each independently, but preferablyidentically, have the same definition and areas of preference as statedunder the formulae (II) and (IV).

Examples of compounds of the formula (XI) include:

methyl N-methylcarbamate, ethyl N-methylcarbamate, methylN-methylcarbamate, ethyl N-methylcarbamate, methyl N,N-dimethylcarbamateand ethyl N,N-dimethyl-carbamate.

Such a reaction is described, for example, in Tetrahedron Lett. 1998,39, 4995 and may, for example, be applied in a similar manner for thereaction of 2-acetylthiophene with methyl N-methylcarbamate or ethylN-methylcarbamate.

The compounds of the formula (IV) which can be used for the processaccording to the invention may likewise be obtained via a base-catalysedreaction of the compounds of the general formula (IX) with isocyanates,as described in Synth. Commun. 1987, 17, 13-18. An example is thereaction of 2-acetylthiophene with methyl isocyanate, ethyl isocyanateor benzyl isocyanate.

For the purposes of the invention, aryl is, for example and withpreference, a carbocyclic aromatic radical or heteroaromatic radicalwhich contains no, one, two or three heteroatoms per cycle, but at leastone heteroatom in the entire heteroaromatic radical, which are selectedfrom the group of nitrogen, sulphur or oxygen. The carbocyclic aromaticradicals or heteroaromatic radicals may also be substituted by up tofive substituents per cycle, each of which is independently, for exampleand with preference, selected from the group of hydroxyl, C₁-C₁₂-alkyl,cyano, COOH, COOM where M is an alkali metal ion or half an equivalentof an alkaline earth metal ion, COO—(C₁-C₁₂-alkyl), COO—(C₄-C₁₀-aryl),CO—(C₁-C₁₂-alkyl), CO—(C₄-C₁₀-aryl), O—(C₁-C₁₂-alkyl), O—(C₄-C₁₀-aryl,N(C₁-C₁₂-alkyl)₂, NH—(C₁-C₁₂-alkyl), fluorine, chlorine, bromine,C₁-C₁₂-fluoroalkyl where fluoroalkyl is a singly, multiply or fullyfluorine-substituted alkyl radical as defined above, CONH₂,CONH—(C₁-C₁₂-alkyl), NHCOO—(C₁-C₁₂-alkyl). The same applies to the arylmoiety of an arylalkyl radical.

For the purposes of the invention, alkyl or alkylene or alkoxy is ineach case independently a straight-chain, cyclic, branched or unbranchedalkyl or alkylene or alkoxy radical which may optionally be furthersubstituted by C₁-C₄-alkoxy radicals. The same applies to the alkylenemoiety of an arylalkyl radical.

In all contexts, C₁-C₆-alkyl is, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, tert-butyl, n-pentyl, cyclohexyl and n-hexyl,C₁-C₈-alkyl is additionally, for example, n-heptyl, n-octyl or isooctyl,C₁-C₁₂-alkyl is further additionally, for example, n-decyl andn-dodecyl, and C₁-C₂₀-alkyl is still further additionally n-hexadecyland n-octadecyl.

For example, C₁-C₄-alkylene in all contexts is preferably methylene,1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene,1,1-butylene, 1,2-butylene, 2,3-butylene and 1,4-butylene, andC₁-C₈-alkylene is additionally 1,5-pentylene, 1,6-hexylene,1,1-cyclohexylene, 1,4-cyclohexylene, 1,2-cyclohexylene and1,8-octylene.

For example, C₁-C₄-alkoxy in all contexts is preferably methoxy, ethoxy,isopropoxy, n-propoxy, n-butoxy and tert-butoxy, and C₁-C₈-alkoxy isadditionally cyclohexyloxy. The general term aryl as a substituentencompasses carbocyclic radicals and heteroaromatic radicals in whichno, one, two or three framework atoms per cycle, but at least oneframework atom in the entire radical, are heteroatoms selected from thegroup of nitrogen, sulphur or oxygen. C₅-C₁₀-Aryl is, for example andwith preference, phenyl, pyridyl, o-, m- or p-tolyl, and C₅-C₁₄-aryl isadditionally anthracenyl.

The same applies to the aryl moiety of an arylalkyl radical.C₆-C₁₅-Arylalkyl is, for example and with preference, benzyl.

For the purposes of the invention, haloalkyl and fluoroalkyl are eachindependently a straight-chain, cyclic, branched or unbranched alkylradical which may be substituted by one or more, or fully by, halogenatoms independently selected from the group of fluorine, chlorine orbromine, and fluorine respectively.

For example and with preference, C₁-C₈-haloalkyl is in all contextspreferably trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,pentafluoroethyl and nonafluorobutyl and C₁-C₈-fluoroalkyl istrifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl andnonafluorobutyl.

Protected formyl means a formyl radical which is protected by convertingto aminal, acetal or a mixed aminalacetal where the aminals, acetals andmixed aminalacetals may be acyclic or cyclic.

For example and with preference, protected formyl is a1,1-(2,5-dioxy)cyclopentylene radical.

In step a) of the process according to the invention, the compounds ofthe formula (II) are converted in the presence of a transition metalcatalyst to enantiomerically enriched compounds of the formula (III), orcompounds of the formula (IV) are converted to enantiomerically enrichedcompounds of the formula (V), and the reaction is effected with hydrogenor a hydrogen-transferring compound or a mixture thereof.

The catalytic reduction of ketones to enantiomerically enrichedsecondary alcohols is known in principle. The reducing agents used arecustomarily molecular hydrogen or, in the case of transferhydrogenations, hydrogen-transferring compounds, for example formic acidor isopropanol.

Step a) may be carried out, for example and with preference, in such away that the compounds of the formula (II) or the compounds of theformula (IV) are reduced by hydrogen in the presence of transition metalcatalysts and optionally solvents which comprise chiral,stereoisomerically enriched ruthenium, rhodium, iridium or palladiumcomplexes, or are obtained by reacting ruthenium, rhodium, iridium orpalladium salts with stereoisomerically enriched ligands.

For example, the asymmetric hydrogenation of aryl β-ketoesters usingRu-phosphine catalysts is described in Tetrahedron 1995, 27, 4801 orOrg. and Organomet. Synth. 1999, 2, 175. An overview article can befound in Tetrahedron Asymmetry 1997, 8, 3327. Ruthenium catalysts havingbinaphthyl or biphenylphosphine ligands are suitable in particular forthe asymmetric hydrogenation, as described in EP 529444, EP 643 065, EP749 973 and EP 764 652.

However, for the process according to the invention, preference is givento carrying out step a) as a transfer hydrogenation.

In a preferred embodiment, step a) is carried out in such a way that thecompounds of the formula (II) or the compounds of the formula (IV) arereacted

-   i) in the presence of a ruthenium-, rhodium- or iridium-containing    catalyst and-   ii) in the presence of at least one amine, at least some of which is    present in protonated form,-   iii) with formic acid, formate or mixtures thereof.-   iv) optionally in the presence of organic solvent.

For example and with preference, the catalysts used are those whichcomprise ruthenium complexes. Preferred ruthenium complexes are thosewhich are obtainable by reacting compounds of the formula (XII) withcompounds of the formula (XIII), or complexes of the formula (XIV).Particular preference is given to using those ruthenium complexes whichare obtainable by reacting compounds of the formula (XII) with compoundsof the formula (XIII). In a preferred embodiment, the molar ratio ofcompounds of the formula (XIII) to compounds of the formula (II) is 2:1to 3:1, particularly preferably 2.01:1 to 2.4:1.

Advantageously, compounds of the formula (XIII) and compounds of theformula (XII) are mixed and the mixture is taken up in organic solvent.The resulting mixture may also, before addition to the reaction mixture,advantageously be stirred with a base, preferably a tertiary amine and,for example and with preference, for 10 to 30 min, and the molar amountof tertiary amine is, for example and with preference, 1:1 to 3:1, morepreferably 1:1 to 2:1, based on compounds of the formula (XIII).

For organic solvents and amines, the same statements and areas ofpreference apply as will be described in detail below.

In the compounds of the formula (XII)

[RuX₂(arene)]₂  (XII),

-   arene is a coordinated aromatic compound having 6 to 12 ring carbon    atoms which may be further substituted by up to 6 radicals, each of    which is independently selected from the group of C₁-C₈-alkyl,    benzyl and phenyl and-   X is, for example and with preference, chlorine, bromine or iodine,    particularly preferably chlorine.

Arene is preferably benzene or naphthalene which may be substituted byup to 6 radicals, each of which is independently selected from the groupof methyl, ethyl, n-propyl, isopropyl and tert-butyl.

Arene is preferably mesitylene, cumene or benzene.

Particularly preferred compounds of the formula (XII) are:

(benzene)dichlororuthenium dimer, (mesitylene)dichlororuthenium dimerand (cumene)dichlororuthenium dimer, and even greater preference isgiven to (cumene)dichlororuthenium dimer.

In the formula (XIII)

-   R⁷ and R⁸ are each independently, for example, C₁-C₂₀-alkyl,    C₄-C₁₅-aryl or C₅-C₁₆-arylalkyl, or R⁷ and R⁸ together are a    straight-chain or branched C₃-C₁₂-alkylene radical, and-   R⁹ is C₁-C₂₀-alkyl, C₁-C₂₀-fluoroalkyl or C₄-C₁₅-aryl.-   R⁷ and R⁸ are preferably identically phenyl or are together    straight-chain C₃-C₈-alkylene, for example 1,3-propylene or    1,4-butylene, and R⁷ and R⁸ are particularly preferably identically    phenyl.-   R⁹ is preferably C₁-C₄-alkyl, C₁-C₄-fluoroalkyl, phenyl or naphthyl    which may be further substituted by no, one, two, three, four or    five radicals which are selected from the group of C₁-C₄-alkyl,    C₁-C₄-alkoxy, C₁-C₄-fluoroalkyl, fluorine and chlorine.-   R⁹ is particularly preferably methyl, trifluoromethyl,    pentafluoroethyl, nonafluorobutyl, phenyl, p-tolyl, p-ethylphenyl,    p-anisyl, p-ethoxyphenyl, p-chlorophenyl, 2,4,6-trimethylphenyl,    2,4,6-triisopropylphenyl, p-fluorophenyl, pentafluorophenyl and    naphthyl.-   R⁹ is very particularly preferably p-tolyl, phenyl, naphthyl.-   R⁹ is even more preferably p-tolyl.

The compounds of the formula (XIII) preferably had a stereoisomericpurity of 90% or more, particularly preferably 95% or more and veryparticularly preferably 98.5% or more.

Examples of compounds of the formula (XIII) include

N-[(1R,2R) and (1S,2S)-2-amino-1,2-diphenylethyl]-p-tolylsulphonamide,N[(1R,2R) and (1S,2S)-2-amino-1,2-diphenylethyl]-o-tolylsulphonamide,N-[(1R,2R) and (1S,2S)-2-amino-1,2-diphenylethyl]-m-tolylsulphonamide,N-[(1R,2R) and (1S,2S)-2-amino-1,2-diphenylethyl]-phenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-4-ethylphenylsulphonamide, N-[(1R,2R)and (1S,2S)-2-amino-1,2-diphenylethyl]-3-ethylphenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-2-ethylphenylsulphonamide, N-[(1R,2R)and(1S,2S)-2-amino-1,2-diphenylethyl]-2,4,6-trimethylphenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-2,4,6-triisopropylphenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-4-chlorophenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-3-chlorophenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-2-chlorophenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-4-fluorophenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-3-fluorophenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-2-fluorophenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-4-methoxyphenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-3-methoxyphenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-2-methoxyphenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-1-naphthylsulphonamide, N-[(1R,2R)and (1S,2S)-2-amino-1,2-diphenylethyl]-2-naphthylsulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-pentafluorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-amino-1,2-diphenylethyl]-methanesulphonamide,N-[(1R,2R) and(1S,2S)-2-amino-1,2-diphenylethyl]-trifluoromethanesulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-p-tolylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-o-tolylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-m-tolylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-phenylsulphonamide, N-[(1R,2R)and (1S,2S)-2-aminocyclohexyl]-4-ethylphenylsulphonamide, N-[(1R,2R) and(1S,2S)-2-aminocyclohexyl]-3-ethylphenylsulphonamide, N-[(1R,2R) and(1S,2S)-2-aminocyclohexyl]-2-ethylphenylsulphonamide, N-[(1R,2R) and(1S,2S)-2-aminocyclohexyl]-2,4,6-trimethylphenylsulphonamide, N-[(1R,2R)and (1S,2S)-2-aminocyclohexyl]-2,4,6-triisopropylphenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-4-chlorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-3-chlorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-2-chlorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-4-fluorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-3-fluorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-2-fluorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-4-methoxyphenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-3-methoxyphenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-2-methoxyphenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-1-naphthylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-2-naphthylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-pentafluorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-methanesulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclohexyl]-trifluoromethanesulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-p-tolylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-o-tolylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-m-tolylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]phenylsulphonamide, N-[(1R,2R)and (1S,2S)-2-aminocyclopentyl]-4-ethylphenylsulphonamide, N-[(1R,2R)and (1S,2S)-2-aminocyclopentyl]-3-ethylphenylsulphonamide, N-[(1R,2R)and (1S,2S)-2-aminocyclopentyl]-2-ethylphenylsulphonamide, N-[(1R,2R)and (1S,2S)-2-aminocyclopentyl]-2,4,6-trimethylphenylsulphonamide,N-[(1R,2R) and(1S,2S)-2-aminocyclopentyl]-2,4,6-triisopropylphenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-4-chlorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-3-chlorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-2-chlorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-4-fluorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-3-fluorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-2-fluorophenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-4-methoxyphenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-3-methoxyphenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-2-methoxyphenylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-1-naphthylsulphonamide,N-[(1R,2R) and (1S,2S)-2-aminocyclopentyl]-2-naphthylsulphonamide,N-[(1R,2R) and(1S,2S)-2-aminocyclopentyl]-pentafluorophenylsulphonamide, N-[(1R,2R)and (1S,2S)-2-aminocyclopentyl]-methanesulphonamide, N-[(1R,2R) and(1S,2S)-2-aminocyclopentyl]-trifluoromethanesulphonamide.

In the formula (XIV)

[RuX₂(arene){(XIII)}]  (XIV),

arene and X each have the definition and areas of preference specifiedunder formula (XII), (XIII) in the formula (XIV) represents compounds ofthe formula (XIII) with the definitions and areas of preferencespecified there.

Compounds of the formula (XIV) include:

-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-p-tolylsulphonamidato-κN]-chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-o-tolylsulphonamidato-κ]-chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-m-tolylsulphonamidato-κN]-chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-phenylsulphonamidato-κN]-chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-ethylphenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-3-ethylphenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-ethylphenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2,4,6-trimethylphenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2,4,6-triisopropylphenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-chlorophenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-3-chlorophenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-chlorophenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-fluorophenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-3-fluorophenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-fluorophenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-3-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)ato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-1-naphthylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-naphthylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-pentafluorophenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-methanesulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-trifluoromethanesulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-p-tolylsulphonamidato-κN]-chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-o-tolylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-m-tolylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-phenylsulphonamidato-κN]-chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-ethylphenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-3-ethylphenylsulphonamidato-κN]chloro[(η¹⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-ethylphenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2,4,6-trimethylphenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2,4,6-triisopropylphenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-chlorophenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-3-chlorophenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-chlorophenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-fluorophenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-3-fluorophenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-fluorophenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-3-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)ato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-1-naphthylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-naphthylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-pentafluorophenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-methanesulphonamidato-κN]-chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-trifluoromethanesulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-p-tolylsulphonamidato-κN]-chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-o-tolylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-m-tolylsulphonamidato-κN]-chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-phenylsulphonamidato-κN]-chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-ethylphenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-3-ethylphenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-ethylphenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2,4,6-trimethylphenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2,4,6-triisopropylphenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-chlorophenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-3-chlorophenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-chlorophenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-fluorophenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-3-fluorophenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-fluorophenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-3-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)ato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-1-naphthylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-2-naphthylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-pentafluorophenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-methanesulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-trifluoromethanesulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-p-tolylsulphonamidato-κN]chloro-[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-m-tolylsulphonamidato-κN]-chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-phenylsulphonamidato-κN]-chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-4-ethylphenylsulphonamidato-κN]-chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-2,4,6-trimethylphenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-4-chlorophenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-3-chlorophenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-4-fluorophenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-3-fluorophenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-4-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-3-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-1-naphthylsulphonamidato-κN]-chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-2-naphthylsulphonamidato-κN]-chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-methanesulphonamidato-κN]-chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-trifluoromethanesulphonamidato-κN]chloro[(η⁶)-benzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-p-tolylsulphonamidato-κN]chloro-[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-m-tolylsulphonamidato-κN]-chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-phenylsulphonamidato-κN]-chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-4-ethylphenylsulphonamidato-κN]-chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-2,4,6-trimethylphenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-4-chlorophenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-3-chlorophenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-4-fluorophenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-3-fluorophenylsulphonamidato-κN]-chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-4-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-3-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-1-naphthylsulphonamidato-κN]-chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-2-naphthylsulphonamidato-κN]-chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-methanesulphonamidato-κN]-chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-trifluoromethanesulphonamidato-κN]chloro[(η⁶)-cumene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-p-tolylsulphonamidato-κN]chloro-[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-m-tolylsulphonamidato-κN]-chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-phenylsulphonamidato-κN]-chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-4-ethylphenylsulphonamidato-κN]-chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-2,4,6-trimethylphenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-4-chlorophenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-3-chlorophenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-4-fluorophenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-3-fluorophenylsulphonamidato-κN]-chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-4-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-3-methoxyphenylsulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-1-naphthylsulphonamidato-κN]-chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-2-naphthylsulphonamidato-κN]-chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-methanesulphonamidato-κN]-chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II)    and-   [N-[(1R,2R and    1S,2S)-2-(amino-κN)-cyclohexyl]-trifluoromethanesulphonamidato-κN]chloro[(η⁶)-1,3,5-trimethylbenzene]ruthenium(II).

Particularly preferred catalysts for step a) are those which compriseruthenium complexes which are obtainable by reacting S,S— orR,R—N-p-toluenesulphonyl-1,2-diphenylethylenediamine and(cumene)dichlororuthenium dimer.

In ii), operation is effected in the presence of at least one amine,preferably one amine, at least some of which is present in protonatedform.

Also formic acid, formates or mixtures thereof are used for ii).

Preference is given to using mixtures of formic acid with amines. Inthis way, the corresponding ammonium formates are at least partiallyformed which can be used in a similar manner.

Useful amines are in particular those of the formula (XV)

NR¹⁰R¹¹R¹²  (XV)

whereR¹⁰, R¹¹ and R¹² are each independently hydrogen, C₁-C₈-alkyl or benzyl.

Particularly preferred amines are ammonia and those of the formula (XV)where R¹⁰, R¹¹ and R¹² are each independently C₁-C₈-alkyl or benzyl.

Particularly preferred amines are those of the formula (XV) where R¹⁰,R¹¹ and R¹² are each identically ethyl, n-butyl or n-hexyl, althougheven greater preference is given to the use of triethylamine.

The molar ratio of formic acid to tertiary amine may be, for example,1:1 to 3:1, and preference is given to a ratio of 1.01:1 to 1.5:1.

The molar ratio of formic acid based on substrate used may be, forexample, 1:1 to 3:1, and preference is given to 1:1 to 1.5:1, particularpreference to 1.02:1 to 1.1:1.

According to iii), step a) may be carried out in the presence orabsence, preferably in the presence, of organic solvents.

Examples of suitable organic solvents include:

amides, for example dimethylformamide, N-methylpyrrolidinone, optionallyhalogenated aliphatic or araliphatic solvents having up to 16 carbonatoms, for example toluene, o-, m- and p-xylene, chloroform,dichloromethane, chlorobenzene, the isomeric dichlorobenzenes,fluorobenzene, nitriles, for example acetonitrile, benzonitrile,dimethyl sulphoxide or mixtures thereof.

Preferred solvents are acetonitrile, N-methylpyrrolidinone, chloroform,dichloromethane, chlorobenzene, the isomeric dichlorobenzenes,fluorobenzene or mixtures thereof, and particular preference is given todichloromethane, acetonitrile, N-methylpyrrolidinone or mixturesthereof.

The reaction temperature may be, for example, −10 to 150° C., andpreference is given to 20 to 100° C., particular preference to 20 to 80°C.

The reaction times are, for example, between 0.5 h and 48 h, preferablybetween 6 and 24 h.

The molar amount of ruthenium may be, for example, 0.01 to 1.0 mol %,based on the substrate used, and preference is given to 0.02 to 0.2 mol%, very particular preference to 0.02 to 0.1 mol %.

It is advantageous, although not obligatory, to carry out the reactionin a substantially oxygen-free atmosphere. Substantially oxygen-freemeans, for example, a content of 0 to 1% by volume, preferably 0 to 0.1%by volume, of oxygen.

The reaction may be accelerated by removing carbon dioxide which isreleased during the reaction. Advantageous, and therefore encompassed bythe invention, is intensive stirring of the reaction mixture at anaverage stirrer speed of, for example, 100 to 3 000 min⁻¹, preferably500 to 1 500 min⁻¹. Alternatively, or supplementarily thereto, theremoval of carbon dioxide may be supported by passing an inert gasstream through or over the reaction mixture. Examples of suitable gasesinclude nitrogen, noble gases, for example argon, or mixtures thereof.

A particularly preferred embodiment of step a) is described hereinbelow,although without imposing any limitation.

In a stirred tank, a 1:1 mixture (molar) of formic acid andtriethylamine is prepared by simple mixing and compounds of the formula(II) or compounds of the formula (IV) are added in equimolar amounts orin a slight deficiency to this biphasic mixture. Depending on thesolubility of the substrate, an amount of an organic solvent is added.The mixture is inertized by passing through nitrogen and the mixture isheated to the desired reaction temperature with vigorous stirring.

The catalyst is added to this mixture as solution in dichloromethane inmolar ratios relative to the substrate of, for example, 1:500 to 1:5000,and the reaction mixture is stirred for the desired time. The conversionis followed chromatographically.

The reaction mixture may subsequently be worked up by processes known tothose skilled in the art. It has proven advantageous to work up thereaction mixture by adding solvents and dilute aqueous hydrochloric acidor water. After phase separation, the product may be isolated in amanner known per se from the organic phase either distillatively or by asuitable crystallization process.

In step a), enantiomerically enriched compounds of the formulae (III) or(V) are obtained with the definitions and areas of preference specifiedabove.

Depending on the choice of the configuration of the ligands, the S- orR-configured products are obtainable, and the configuration informationrelates to the carbon atom adjacent to the Ar radical.

The compounds of the formulae (III) or (V) may be isolated or furtherreacted directly. For intermediate isolation, the reaction mixture maybe separated, for example, between water and an organic solvent of lowwater miscibility, and the desired product transferred to the organicphase. After the removal of the organic solvent, a crude product isobtained which may be purified, for example, by crystallization ordistillation.

When compounds of the formula (II) have been used for step a),enantiomerically enriched compounds of the formula (III) are obtainedwhich are reacted in step b) with amines of the formula (VI) and havingthe definitions and areas of preference specified there.

This may be effected, for example, in such a way that theenantiomerically enriched compounds of the formula (III) are reactedwith the amines of the formula (VI), optionally in a solvent. Anoverview of the synthesis of carboxamides from carboxylic acids,carboxylic esters, carboxylic anhydrides and other carboxamides can befound in Houben-Weyl, 4th edition, volume E 5, 941-1010.

In the case of liquid and gaseous amines, the use of solutions of theamines is suitable. For example, in the case of methylamine, solutionsof methylamine in water, methanol or in ethanol may advantageously beused for the reaction of carboxylic esters of the formula (III). For theconversion of free carboxylic acids of the formula (III) to the amidesof the formula (V), examples of suitable reactions are those of aminesof the general formula (VI) in the presence of coupling reagents such as2-halopyridinium or -1,3-thiazolium salts, or in the presence of acidiccation exchangers.

It is also possible to convert a compound of the formula (V) to apreferred compound of the formula (V). This may be effected, forexample, by transamidation, N-alkylation or N-dealkylation.

In step b), enantiomerically enriched compounds of the formula (V) arethen obtained from enantiomerically enriched compounds of the formula(III).

The scope of the invention also encompasses the following compounds ofthe formula (V):

(S)-3-Hydroxy-3-(2-thiophen-yl)-N-methylpropionamide,(R)-3-hydroxy-3-(2-thiophen-yl)-N-methylpropionamide, and any desiredmixtures of these compounds, for example the racemate.

Particular mention is made of(S)-3-hydroxy-3-(2-thiophen-yl)-N-methylpropionamide.

The enantiomerically enriched compounds of the formula (V) may then bereduced to the enantiomerically enriched compounds of the formula (I).The reduction of carboxamides to the corresponding amines is known inprinciple and illustrated by way of summary in Houben Weyl “Methoden derOrganischen Chemie”, 4th edition, volume E 16 d, 987-1003.

Preference is given to the reaction of compounds of the formula (V) withcomplex boron or aluminium hydrides, for example lithium aluminiumhydride, Red-Al® (sodium bis(2-methoxyethoxy)dihydroaluminate) or sodiumborohydride.

Particular preference is given to the reaction of compounds of theformula (V) with lithium aluminium hydride.

Step c) is preferably carried out at temperatures in the range from 0 to150° C., more preferably in the range from 50 to 110° C. Customarily,the reductions are carried out in ethers as solvents, preferably incyclic ethers such as tetrahydrofuran or dioxane, or the reductions withRed-Al® can equally be carried out in toluene as solvent.

In the manner according to the invention, the enantiomerically enrichedcompounds of the formula (I)

whereAr, R¹ and R² each have the definitions and areas of preferencespecified above.

Individual compounds of the formula (I) include:

(1S)-3-(methylamino)-1-(2-thiophen-yl)-1-propanol,(1R)-3-(methylamino)-1-(2-thiophen-yl)-1-propanol,(1S)-3-(dimethylamino)-1-(2-thiophen-yl)-1-propanol,(1R)-3-(dimethylamino)-1-(2-thiophen-yl)-1-propanol,(1S)-3-(methylamino)-1-(phenyl)-1-propanol,(1R)-3-(methylamino)-1-(phenyl)-1-propanol,(1S)-3-(methylamino)-1-(4-tolyl)-1-propanol and(1R)-3-(methylamino)-1-(4-tolyl)-1-propanol.

The enantiomerically enriched compounds of the formula (I) which can beprepared according to the invention are suitable in particular forpreparing enantiomerically enriched compounds of the formula (XVI)

aryl-CH(OR¹⁰)—CH₂—CH₂NR¹R²  (XVI)

where aryl, R¹ and R² each have the definition and areas of preferencespecified under the formula (I) andR¹⁰ is phenyl or naphthyl which may be not at all, singly or multiplysubstituted by substituents which are each independently selected fromthe group of cyano, CO—(C₁-C₁₂-alkyl), O—(C₁-C₁₂-alkyl), (C₁-C₁₂-alkyl),fluorine, chlorine, bromine, C₁-C₁₂-fluoroalkyl where fluoroalkyl is asingly, multiply or fully fluorine-substituted alkyl radical.

R¹⁰ is preferably naphthyl.

Preferred compounds of the formula (XVI) are:

(S)—N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine and(R)—N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine and salts ofboth and also(S)—Nmethyl-3-(4-trifluoromethylphenyloxy)-3-(2-phenyl)propylamine and(R)—N-methyl-3-(4-trifluoromethylphenyloxy)-3-(2-phenyl)propylamine andalso mixtures of both (e.g. the racemate) and their salts, and also(S)—N-methyl-3-(2-tolyloxy)-3-(2-phenyl)propylamine and(R)—N-methyl-3-(2-tolyloxy)-3-(2-phenyl)propylamine and also mixtures ofboth (e.g. the racemate) and their salts, although particular preferenceis given to (S)—N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine.

The scope of the invention therefore also encompasses a process which,as step

-   d) encompasses the reaction of compounds of the formula (I) with    compounds of the formula (XVII) in the presence of a base.

In formula (XVII)

R¹⁰-Hal  (XVII)

R¹⁰ has the definition and areas of preference specified under theformula (XVI) and Hal is fluorine, chlorine, bromine or iodine,preferably fluorine.

The compounds of the formula (XVII) used are preferably1-fluoronaphthalene and 4-chlorobenzotrifluoride.

Useful bases are those which can at least partially deprotonate thecompounds of the formula (I) at the alcohol function.

Preferred bases are alkali metal hydroxides and hydrides, for examplesodium hydride, optionally with the addition of potassium benzoate orpotassium acetate, as described in U.S. Pat. No. 5,362,886, sodiumhydroxide and potassium hydroxide.

The compounds of the formulae (I), (V) and (XVI) are suitable inparticular for preparing pharmaceuticals, such as preferably serotoninor noradrenaline takeup inhibitors.

The process according to the invention has the advantage that it ispossible, starting from reactants which are easily obtainable, tosynthesize enantiomerically enriched 1-aryl-3-aminopropanols of theformula (I) and their subsequent products in high overall yields, highenantiomeric excesses and high purities on the industrial scale.

EXAMPLES Example 1

In a 2 l flask, 180.8 g of sodium methoxide and 1500 ml of toluene wereheated to 100° C. and a solution of 257 g of 2-acetylthiophene in 510 mlof dimethyl carbonate was then added dropwise within 4 hours. Themethanol formed in the reaction was distilled off as an azeotrope. In a4 l flask, 120 ml of conc. sulphuric acid in 900 g of ice was initiallycharged and the cooled reaction mixture was added in such a way that 40°C. was not exceeded. Stirring was continued and the pH was adjusted topH 1. The phases were separated and the organic phase was extractedthree times with aqueous sodium sulphate solution and then concentratedunder reduced pressure. The vacuum distillation of the crude productdelivered 278 g of methyl β-oxo-(2-thiophene)propionate as atransparent, light yellow liquid (98% pure by GC, 74% of theory).

Example 2 Methyl (3S)-3-hydroxy-3-(2-thienyl)propanoate

In a Schlenk vessel, the catalyst solution is prepared by weighing 314mg (2.03 equiv.) of S,S-TsDPEN and 263 mg of [(cumene)RuCl₂]₂ in 10 mlof CH₂Cl₂ and also admixing with 0.3 ml (2 equiv.) of Et₃N and stirringthis mixture at room temperature for 15 min.

In a 1 l multinecked flask equipped with a sparging stirrer, refluxcondenser and internal thermometer, an HCOOH/Et₃N mixture (molar ratio1:1) is prepared by gradually adding 41 ml of HCOOH dropwise within 20min to 152 ml of Et₃N with stirring and ice cooling. 190 g of methyl2-oxo-3-(2-thienyl)propionate are added to this biphasic mixture, thehomogeneous yellow solution is admixed with 0.1 l of dichloromethane andthe entire mixture is degassed by passing through argon for 20 min. Itis heated to 36° C. and the dark red catalyst solution is added all atonce to the reaction mixture with vigorous stirring. Stirring iseffected at 800 rpm while passing argon through the reaction mixture for14 h.

After diluting with 0.3 l of 1N HCl and 0.3 l of CH₂Cl₂ and phaseseparation, the H₂O phase is extracted 2× more with CH₂Cl₂, the combinedorganic phases are washed with 150 ml of NaCl solution, dried overMgSO₄, filtered and the solvent is removed. The crude product is usedwithout purification in the next stage 100% conversion.

The conversion and enantiomer analysis were effected by gaschromatography on an HP gas chromatograph using an IVADEX capillarycolumn (12.5 m, 0.3 μm layer thickness using individual temperatureprogrammes).

¹H NMR (d1-chloroform, 400 MHz): δ=7.23 (m, 1H, Ar—H), 6.95 (m, 2H,Ar—H), 5.36 (dd, 1H, CHOH), 3.71 (s, 3H, OCH₃), 2.86 (m, 2H, CHH) ppm.

¹³C NMR (d1-chloroform, 100 MHz): δ=185.3 (C═O), 146.8 (C, Ar), 127.1(CH, Ar), 125.3 (CH, Ar), 124.1 (CH, Ar), 66.9 (CHOH), 52.4 (CH3), 43.5(CH2) ppm.

Chiral GC: 14.05, 14.41 min. ee=98.2%.

Example 3

115 g of methyl (3S)-3-hydroxy-3-(2-thienyl)propanoate are initiallycharged and admixed with 618 ml of a 2 molar methanolic methylaminesolution. This mixture is stirred at 60° C. for 4 h, cooled and thenconcentrated under reduced pressure. In this way, 118 g ofN-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide (purity 86%; 88% oftheory) are obtained. The crude product may be used in the next stage orelse recrystallized from methylene chloride and hexane. This delivered93 g of N-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide (76% of theory)as white crystals. As an alternative, the purification may also be doneby distillation.

The conversion and enantiomer analysis were effected by gaschromatography on an HP gas chromatograph using an IVADEX capillarycolumn (12.5 m, 0.3 μm layer thickness using individual temperatureprogrammes).

Example 4

1728 ml of dry tetrahydrofuran are initially charged with 52 g oflithium aluminium hydride and heated to reflux. At the same time,dropwise addition of 86.4 g ofN-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide dissolved in 692 g oftetrahydrofuran is commenced. Once dropwise addition is complete,stirring is continued under reflux overnight. The reaction mixture isthen cooled to room temperature and 1037 ml of water are cautiouslyadded dropwise. 173 ml of a 10% sodium hydroxide solution were thenadded dropwise and the solution was filtered. The solvent was removedunder reduced pressure. The crude solution was admixed with 346 ml of 1N sodium hydroxide solution extracted 3 times with 345 ml of tolueneeach time. The organic phases are combined and the volatile constituentsare removed under reduced pressure to obtain 76 g of(1S)-3-(methylamino)-1-(2-thienyl)-1-propanol (84% purity, 80% oftheory).

1. Process for preparing enantiomerically enriched compounds of theformula (IAr—CH(OH)—CH₂—CH₂—NR¹R²  (I) where Ar is a substituted or unsubstitutedaryl radical and R¹ and R² are each independently hydrogen,C₁-C₂₀-alkyl, C₄-C₁₄-aryl or C₅-C₁₅-arylalkyl, or the two R¹ and R²radicals together are C₃-C₁₂-alkylene, characterized in that a)compounds of the formula (II) are converted to enantiomerically enrichedcompounds of the formula (III) or compounds of the formula (IV) areconverted to enantiomerically enriched compounds of the formula (V)Ar—CO—CH₂—COOR³  (II)Ar—CH(OH)—CH₂—COOR³  (III)Ar—CO—CH₂—CONR¹R²  (IV)Ar—CH(OH)—CH₂—CONR¹R²  (V) where, in each case, Ar is as defined underthe formula (I) and R¹ and R² are each as defined under the formula (I)and R³ is hydrogen, C₁-C₂₀-alkyl, C₄-C₁₄-aryl or C₅-C₁₅-arylalkyl, andwhere the reaction is effected in the presence of a transition metalcatalyst with hydrogen or a hydrogen-transferring compound or a mixturethereof and b) in the case that compounds of the formula (II) have beenused for step a), the enantiomerically enriched compounds of the formula(III) are reacted with amines of the formula (VI)HNR¹R²  (VI) where R¹ and R² are each as defined under the formula (I)to give enantiomerically enriched compounds of the formula (V) asdefined above and c) the enantiomerically enriched compounds of theformula (V) are converted by reduction to enantiomerically enrichedcompounds of the formula (I) as defined above.
 2. Process according toclaim 1, characterized in that d) the enantiomerically enrichedcompounds of the formula (I) are reacted in the presence of a base withcompounds of the formula (XVII)R¹⁰-Hal  (XVII) where R¹⁰ is phenyl or naphthyl which is not at all,singly or multiply substituted by substituents which are eachindependently selected from the group of cyano, CO—(C₁-C₁₂-alkyl),O—(C₁-C₁₂-alkyl), (C₁-C₁₂-alkyl), fluorine, chlorine, bromine,C₁-C₁₂-fluoroalkyl, where fluoroalkyl is a singly, multiply or fullyfluorine-substituted alkyl radical and Hal is fluorine, chlorine,bromine or iodine to give compounds of the formula (XVI)Ar—CH(OR¹⁰)—CH₂—CH₂—NR¹R²  (XVI) where Ar, R¹, R² and R¹⁰ are each asdefined above.
 3. Process according to one or more of claims 1 to 2,characterized in that compounds of the formula (II) as defined in claim1 are used in step a).
 4. Process according to one or more of claims 1to 3, characterized in that Ar in the formulae (I) to (V) is acarbocyclic aromatic radical having 6 to 24 framework carbon atoms or aheteroaromatic radical having 4 to 24 framework carbon atoms in whichno, one, two or three framework carbon atoms per cycle, but at least oneframework carbon atom in the entire heteroaromatic radical, aresubstituted by heteroatoms selected from the group of nitrogen, sulphuror oxygen, and where the carbocyclic aromatic radicals or heteroaromaticradicals are substituted by up to five identical or differentsubstituents per cycle selected from the group of hydroxyl, fluoro,nitro, cyano, free or protected formyl, C₁-C₁₂-alkyl, C₁-C₁₂-haloalkyl,C₅-C₁₄-aryl, C₆-C₁₅-arylalkyl, —PO—[(C₁-C₈)-alkyl]₂,—PO—[(C₅-C₄)-aryl]₂, —PO—[(C₁-C₈)-alkyl)(C₅-C₁₄)-aryl)],tri(C₁-C₈-alkyl)siloxyl or a radical of the general formula (VII)A-B-D-E  (VII) where, each independently, A is missing or is aC₁-C₈-alkylene radical and B is missing or is oxygen, sulphur or NR⁴,where R⁴ is hydrogen, C₁-C₈-alkyl, C₆-C₁₅-arylalkyl or C₅-C₁₄-aryl and Dis a carbonyl group and E is R⁵, OR⁵, NHR⁶ or N(R⁶)₂, where R⁵ isC₁-C₈-alkyl, C₆-C₁₅-arylalkyl, C₁-C₈-haloalkyl or C₅-C₁₄-aryl and R⁶ isin each case independently C₁-C₈-alkyl, C₆-C₁₅-arylalkyl or C₆-C₁₄-aryl,or N(R⁶)₂ together is a cyclic amino radical, or a radical of thegeneral formulae (VIIIa-e)A-E  (VIIIa)A-SO₂-E  (VIIIb)A-B-SO₂R²  (VIIIc)A-SO₃W  (VIIId)A-COW  (VIIIe) where A, B, E and R² are each as defined above and W isOH, NH₂ or OM where M is an alkali metal ion, half an equivalent of analkaline earth metal ion, an ammonium ion or an organic ammonium ion. 5.Process according to one or more of claims 1 to 4, characterized in thatAr in the formulae (I) to (V) is 2-thiophen-yl.
 6. Process according toone or more of claims 3 to 5, characterized in that the compounds of theformula (II) used are: methyl 3-oxo-3-(2-thienyl)propanoate, ethyl3-oxo-3-(2-thienyl)propanoate, isopropyl 3-oxo-3-(2-thienyl)propanoate,tert-butyl 3-oxo-3-(2-thienyl)propanoate, 2-ethylhexyl3-oxo-3-(2-thienyl)propanoate, methyl 3-oxo-3-(phenyl)propanoate, ethyl3-oxo-3-(phenyl)propanoate, isopropyl 3-oxo-3-(phenyl)propanoate,tert-butyl 3-oxo-3-(phenyl)propanoate, 2-ethylhexyl3-oxo-3-(phenyl)propanoate, methyl 3-oxo-3-(4-tolyl)propanoate, ethyl3-oxo-3-(4-tolyl)propanoate, isopropyl 3-oxo-3-(4-tolyl)propanoate,tert-butyl 3-oxo-3-(4-tolyl)propanoate or 2-ethylhexyl3-oxo-3-(4-tolyl)propanoate.
 7. Process according to one or more ofclaims 1 to 6, characterized in that the compounds of the formula (II)have been obtained by reacting compounds of the formula (IX)Ar—CO—CH₃  (IX) where Ar has the same definition and areas of preferencespecified under the formula (I) with compounds of the formula (X)R³—O—CO—OR³  (X) where the R³ radicals each independently have the samedefinition and areas of preference as stated under the formula (II). 8.Process according to one or more of claims 1 to 7, characterized in thatthe compounds of the formula (III) have been obtained by reactingcompounds of the formula (IX)Ar—CO—CH₃  (IX) where Ar has the definition and areas of preferencespecified under the formula (I) with compounds of the formula (XI)R³—O—CO—NR¹R²  (XI) where the R¹, R² and R³ radicals each independentlyhave the same definition and areas of preference as stated under theformulae (II) and (III).
 9. Process according to one or more of claims 1to 8, characterized in that step a) is carried out in such a manner thatthe compounds of the formula (II) or the compounds of the formula (IV)are reacted i) in the presence of a ruthenium-, rhodium- oriridium-containing catalyst and ii) in the presence of at least oneamine, at least some of which is present in protonated form, iii) withformic acid, formate or mixtures thereof.
 10. Process according to claim9, characterized in that the catalysts used are those which compriseruthenium complexes.
 11. Process according to claim 10, characterized inthat the ruthenium complexes used are those obtainable by reactingcompounds of the formula (XII) with compounds of the formula (XIII), orcomplexes of the formula (XIV) where, in the compounds of the formula(XII)[RuX₂(arene)]₂  (XII), arene is a coordinated aromatic compound having 6to 12 ring carbon atoms which may be further substituted by up to 6radicals, each of which is independently selected from the group ofC₁-C₈-alkyl, benzyl and phenyl and X is chlorine, bromine or iodine, andwhere, in the formula (XIII)

R⁷ and R⁸ are each independently, for example, C₁-C₂₀-alkyl, C₄-C₁₅-arylor C₅-C₁₆-arylalkyl, or R⁷ and R⁸ together are a straight-chain orbranched C₃-C₁₂-alkylene radical, and R⁹ is C₁-C₂₀-alkyl,C₁-C₂₀-fluoroalkyl or C₄-C₁₅-aryl, and where, in the formula (XIV)[RuX₂(arene){(XIII)}]  (XIV), arene and X are each as defined underformula (XII) and (XIII) represents compounds of the formula (XIII) asdefined there.
 12. Process according to one or more of claims 10 and 11,characterized in that the ruthenium complexes used are those which areobtainable by reacting S,S— orR,R—N-p-toluenesulphonyl-1,2-diphenylethylenediamine and(cumene)dichlororuthenium dimer.
 13. Process according to one or more ofclaims 10 to 12, characterized in that mixtures of formic acid andtriethylamine are used.
 14. Process according to one or more of claims10 to 13, characterized in that the reaction temperature is −10 to 150°C.
 15. Process according to one or more of claims 10 to 14,characterized in that the molar amount of ruthenium is 0.01 to 1.0 mol%, based on the substrate used.
 16. Process according to one or more ofclaims 10 to 15, characterized in that the reduction in step c) iscarried out with lithium aluminium hydride. 17.(S)-3-Hydroxy-3-(2-thiophen-yl)-N-methylpropionamide,(R)-3-hydroxy-3-(2-thiophen-yl)-N-methylpropionamide, and the racemicand any desired mixture of these compounds.
 18. Use of anenantiomerically enriched compound of the formulae (I), (V) and (XVI) asdefined in claims 1 and 2 for preparing pharmaceuticals.